CTX001 for Sickle Cell Disease and Thalassemia

Recruiting at 14 trial locations

Overseen By Medical Information

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Vertex Pharmaceuticals Incorporated

Disqualifiers: Prior HSCT, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CTX001 for individuals with transfusion-dependent β-thalassemia or severe sickle cell disease. Researchers aim to determine if this treatment, which modifies patients' own blood stem cells using CRISPR (a gene-editing tool), is safe and effective. It targets those who require regular blood transfusions or experience frequent severe pain episodes due to sickle cell disease. Participants must have had these conditions for some time and meet specific health criteria. As a Phase 3 trial, this represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. Please consult with the trial investigators for more details.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

Is there any evidence suggesting that CTX001 is likely to be safe for humans?

Research has shown that CTX001, a treatment for sickle cell disease and thalassemia, is proving to be safe. Studies have found that patients receiving CTX001 experience significant benefits without major safety issues. In one study, all five patients with transfusion-dependent β-thalassemia (TDT) did not need transfusions starting about two months after treatment. Additionally, two patients with severe sickle cell disease (SCD) have not experienced any pain crises (severe pain episodes due to blocked blood flow) after treatment.

Further research supports these findings, as the FDA has approved CTX001 for severe sickle cell disease. This approval indicates that the treatment is generally safe and well-tolerated by patients. While every treatment can have some risks, the evidence so far shows that CTX001 is a promising option for people with these conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for sickle cell disease and thalassemia focus on managing symptoms or boosting red blood cell production. However, CTX001 is different because it uses CRISPR-Cas9 gene editing to modify the patient's own stem cells, targeting the BCL11A gene enhancer specific to red blood cells. This approach aims to correct the underlying genetic issue, potentially offering a one-time treatment that could provide long-term benefits. Researchers are excited because this could significantly reduce or even eliminate the need for ongoing treatments, transforming how these genetic disorders are managed.

What evidence suggests that CTX001 might be an effective treatment for sickle cell disease and thalassemia?

Research has shown that CTX001, the investigational treatment in this trial, holds promise for treating sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). In earlier studies, nearly all patients with TDT no longer needed transfusions after receiving CTX001. For those with SCD, the treatment stopped painful episodes caused by blocked blood flow in all patients. Another study found that 97% of patients remained free from these painful episodes for at least 12 months. The treatment uses a method called CRISPR-Cas9 to alter genes in stem cells, helping the body produce healthier blood cells. These results suggest that CTX001 could serve as an effective, one-time treatment for these conditions. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for individuals with transfusion-dependent β-thalassemia or severe sickle cell disease who are eligible for a stem cell transplant. It's not open to those with prior transplants, available matched donors, certain genetic conditions like α-thalassemia in TDT patients, or untreated moyamoya syndrome in SCD patients.

Inclusion Criteria

I am considered suitable for a stem cell transplant by my doctor.

I have severe sickle cell disease and have had at least two severe pain crises per year for the last two years.

I have been diagnosed with TDT and need regular blood transfusions.

Exclusion Criteria

Participants with TDT and SCD: A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor is available per investigator's judgement. Prior hematopoietic stem cell transplant (HSCT). Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.

I have TDT with specific genetic changes or sickle cell β-thalassemia.

I have sickle cell disease and moyamoya syndrome that hasn't been treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of autologous CRISPR-Cas9 modified CD34+ hHSPCs (CTX001) through a central venous catheter

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after receiving the CTX001 infusion

6 months

What Are the Treatments Tested in This Trial?

Interventions

• CTX001

Trial Overview The study tests CTX001, which involves editing the patient's own stem cells using CRISPR-Cas9 technology and then returning them to the body. The goal is to see if this single-dose treatment can safely improve symptoms of these blood disorders.

How Is the Trial Designed?

Group I: CTX001 Experimental Treatment 1 Intervention

CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants will receive a single infusion of CTX001 through a central venous catheter.

CTX001 is already approved in European Union, United States for the following indications:

Approved in European Union as CTX001 for:

• Transfusion-dependent β-thalassemia (TDT)
• Severe sickle cell disease (SCD)

Approved in United States as CTX001 for:

• Transfusion-dependent β-thalassemia (TDT)
• Severe sickle cell disease (SCD)

Who Is Running the Clinical Trial?

Vertex Pharmaceuticals Incorporated

Lead Sponsor

Trials

267

Recruited

36,100+

Dr. David Altshuler

Vertex Pharmaceuticals Incorporated

Chief Medical Officer since 2020

MD, PhD

Dr. Reshma Kewalramani

Vertex Pharmaceuticals Incorporated

Chief Executive Officer since 2020

MD, trained in internal medicine and nephrology

CRISPR Therapeutics

Industry Sponsor

Trials

7

Recruited

630+

Published Research Related to This Trial

In a study analyzing 6,500 blood samples, researchers found that the Xmn1 polymorphism significantly influences the severity of β-thalassemia and sickle cell anemia (SCA), with different genotypes showing varying levels of HbF (fetal hemoglobin).

Individuals with the TT genotype of the Xmn1 polymorphism exhibited higher HbF levels, which correlated with milder clinical symptoms in both β-thalassemia and SCA, suggesting that this genetic variant can help ameliorate disease severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Xmn1 -158 γG variant with severity and HbF levels in β-thalassemia major and sickle cell anaemia. Dadheech, S., Jain, S., Madhulatha, D., et al.[2021]

In a study of 220 transfusion-dependent beta-thalassemia patients, those treated with the oral iron chelator deferasirox (Exjade®) showed significantly higher compliance and convenience compared to those receiving the standard treatment, deferoxamine (DFO).

While both treatments had comparable efficacy, nearly 45% of patients on DFO reported irritation and pain at the injection site, highlighting Exjade® as a potentially preferable option for iron chelation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compliance and satisfaction with deferasirox (Exjade®) compared with deferoxamine in patients with transfusion-dependent beta-thalassemia. Haghpanah, S., Zarei, T., Zahedi, Z., et al.[2022]

Hydroxyurea (HU) treatment significantly reduces the frequency of vaso-occlusive crises (VOC) and acute chest syndrome (ACS) in sickle cell disease (SCD) patients, with improvements observed across all SCD phenotypes in a study of 140 patients.

Both groups receiving HU showed increased fetal hemoglobin (HbF) levels and lower white blood cell counts, indicating that even sub-therapeutic doses (<15 mg/kg/day) can be beneficial, although higher doses (≥15 mg/kg/day) were more commonly maintained or increased.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Administration of Hydroxyurea (HU) Benefits Caucasian Patients with Sickle-Beta Thalassemia. Di Maggio, R., Hsieh, MM., Zhao, X., et al.[2018]

In a study of 26 β-thalassemic patients, it was found that regular blood transfusions were necessary to maintain hemoglobin levels above 10 g/dL, but poor adherence to iron chelation therapy led to significant complications, including cardiac and liver issues.

The study highlighted that 54% of patients experienced failure to thrive due to anemia, indicating a need for improved monitoring and adherence to treatment protocols to enhance the quality of care for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinico-biological and immunohaematological profile of patients with β-thalassemia in Tunisia: about 26 cases]. Romdhane, H., Amara, H., Abdelkefi, S., et al.[2018]

A variant in the KLF4 gene (rs2236599) is linked to the effectiveness of hydroxyurea (HU) treatment in patients with sickle cell disease and β-thalassemia, suggesting it could serve as a pharmacogenomic biomarker for treatment response.

Two variants in the KLF10 gene (rs980112, rs3191333) are associated with sustained fetal hemoglobin (HbF) levels in nontransfusion dependent β-thalassemia patients, indicating their potential as prognostic biomarkers for disease severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomic variants in members of the Krüppel-like factor gene family are associated with disease severity and hydroxyurea treatment efficacy in β-hemoglobinopathies patients. Stratopoulos, A., Kolliopoulou, A., Karamperis, K., et al.[2021]

In a study of 29 patients with β-thalassaemia intermediate, those treated with hydroxyurea showed significant improvements in hemoglobin levels and a decrease in blood transfusion dependency, with an effective treatment rate of 85.71%.

No serious side reactions were reported in patients receiving hydroxyurea, indicating it is a safe treatment option, although long-term effects need further monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Curative Effects of Hydroxyurea on the Patients with β-thalassaemia Intermadia]. Huang, L., Yao, HX.[2018]

In a study of 103 beta-thalassemia patients (83 heterozygous and 20 homozygous) compared to 117 controls, the wild-type homozygous (AA) genotype was found more frequently in beta-thalassemia patients, indicating a potential genetic predisposition.

Despite the prevalence of certain clinical manifestations like iron overload and splenomegaly in beta-thalassemia homozygotes, the FOXO3 SNP rs3800231 did not significantly influence these clinical outcomes, suggesting it may not be a key modifier of disease severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of FOXO3 polymorphism (rs3800231) and clinical subphenotypes of beta thalassemic individuals. Torres, FF., Bernardo, VS., Silva, DGH., et al.[2022]

The management of beta-thalassemia major primarily involves regular blood transfusions and iron chelation therapy, with limited studies available on the safety of these treatments, highlighting a need for more research.

Current treatments, including iron chelators and the erythrocyte maturation agent luspatercept, have been reviewed for safety, but only eleven observational studies were found for iron chelators, indicating a significant gap in comprehensive safety data for these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug safety in thalassemia: lessons from the present and directions for the future. Grech, L., Sultana, J., Borg, K., et al.[2021]

The study demonstrates that targeting specific mutations in thalassemia, such as IVS1-110G>A and IVS2-654C>T, using advanced gene-editing techniques (Cas9 and Cas12a/Cpf1) in hematopoietic stem cells can effectively restore normal gene function.

This approach shows high efficiency in correcting mutations and reversing abnormal splicing in blood cells, suggesting it could significantly benefit patients with transfusion-dependent β-thalassemia by potentially reducing their need for transfusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia. Xu, S., Luk, K., Yao, Q., et al.[2022]

Using CRISPR-Cas9 to edit the BCL11A enhancer in CD34+ cells from two patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) resulted in over 80% successful gene modification without off-target effects.

Both patients showed significant clinical improvements, including high levels of fetal hemoglobin, transfusion independence, and elimination of vaso-occlusive episodes in the SCD patient, more than a year after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. Frangoul, H., Altshuler, D., Cappellini, MD., et al.[2021]

Traditional treatment for β-thalassemia major, such as allogeneic bone marrow transplantation, faces challenges like a limited number of matched donors and risks of immunological complications, prompting the need for new therapies.

Gene editing tools, including CRISPR and zinc-finger nucleases, show promise in treating β-thalassemia by enabling targeted modifications to enhance hemoglobin production and regulate gene expression, offering potential alternatives to current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Editing-Based Technologies for Beta-hemoglobinopathies Treatment. Rahimmanesh, I., Boshtam, M., Kouhpayeh, S., et al.[2022]

In a study of 181 patients with non-transfusion-dependent β-thalassemia, hydroxyurea (HU) demonstrated long-term efficacy, with 82.3% of patients achieving sustained transfusion independence over an average treatment duration of 18.2 years.

Hydroxyurea was found to be safe, with only mild and transient adverse events reported in 33% of patients, and no serious complications or secondary malignancies observed, indicating its suitability for long-term use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent β-thalassemia: a comprehensive single-center experience. Karimi, M., Zarei, T., Bahmanimehr, A., et al.[2021]

In a study of 49 pediatric patients with β-thalassemia major undergoing stem cell transplantation, the addition of ruxolitinib to standard GVHD prophylaxis significantly reduced the incidence of severe grade III-IV acute GVHD compared to the control group (0% vs. 27.3%).

The ruxolitinib group also showed higher overall survival rates (96.3%) and thalassemia-free survival (96.3%) over two years compared to the control group (90.9%), suggesting that ruxolitinib may enhance patient outcomes post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of ruxolitinib in Graft-versus-Host disease prophylaxis for pediatric β-Thalassemia major patients after allogeneic stem cell transplantation: A retrospective cohort study. Hong, X., Chen, Y., Lu, J., et al.[2023]

Ruxolitinib therapy in 22 children with thalassemia after stem cell transplantation effectively reduced the incidence and severity of graft-versus-host disease (GVHD), with no transplant-related deaths reported.

The treatment did not negatively impact hematopoietic recovery and improved overall survival, indicating its potential as a safe and effective option for managing post-transplant complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The Clinical Observation with Ruxolitinib as Graft-Versus-Host Disease Prophylaxis for Children with Thalassemia after Unrelated or Haploidentical Allo-Hematopoietic Stem Cell Transplantation]. Chen, YM., Hong, XL., Lin, JZ., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03745287

A Safety and Efficacy Study Evaluating CTX001 in Subjects ... The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.

2. ir.crisprtx.com ir.crisprtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-present-new-data-22-patients

Press Release These results add to the growing body of evidence that CTX001 may hold the promise for a one-time functional cure for sickle cell disease and beta thalassemia.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10112499/

5612617 EFFICACY AND SAFETY OF A SINGLE DOSE ... Exa-cel infusion led to elimination of transfusions in almost all patients with TDT and elimination of VOCs in all patients with SCD.

4. ashpublications.org ashpublications.org/ashclinicalnews/news/8012/Full-Results-of-Exa-Cel-Study-Show-Continued

Full Results of Exa-Cel Study Show Continued Safety, Efficacy ... The study met both its primary and secondary endpoints: of the 30 evaluable patients, 97% were free from VOCs for at least 12 consecutive months, and 100% were ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2031054

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β ... The CTX001 infusion, which consisted of two manufacturing lots, had allelic editing frequencies of 82.6% and 78.7%, respectively. After the ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118692341

Safety and Efficacy of CTX001 in Patients with Transfusion- ... All 5 patients with TDT have been transfusion-free since ~2 months after CTX001 infusion and the 2 patients with severe SCD have had no VOCs ...